The objective of this project has been to examine the patterns and levels of naturally occurring DNA sequence variation in and around a dense cluster of lethal-mutable genes in Drosophila melanogaster. Of particular interest was the affect of sequence alternations within and flanking the gene encoding the enzyme dopa decarboxylase (Ddc). No clear patterns between sequence variants and Ddc expression were obsserved, despite two-fold variation in DDC enzyme activity among the 46 lines examined. Located adjacent to the 30 - 40 kilobases of DNA sequence containing the dense cluster of eight lethal-mutable genes (including Ddc) is an approximately 40 kilobase region in which, at most, one gene appears to be located. We were interested in levels of sequence variation, particularly deletions and insertions (including transposable elements), in this latter region. If mutations occur randomly throughout the genome, yet persist for any length of time only in regions where they produced little or no deleterious effect, we should see less variation in the dense cluster of genes than in the adjacent 40 kb region. Examination of DNA sequence variation by restriction mapping in this 80 kilobase region has revealed the opposite pattern. Virtually no variation was observed in the genetically sparse region while numerous insertions/deletions in the region containing the dense cluster of genes. While we cannot rule out the selective maintenance of variation in the gene cluster, these results raise the possibility of increased insertion/deletion mutational activity in transcriptionally active regions although unknown constraints may exist in the nonvariable region. We are testing these hypotheses in several other regions of the Drosophila genome.